The goal of this Program-Project Grant (PPG) is to use the tools of modern genetics to elucidate the basic mechanisms that underlie the early stages of hepatocellular carcinogenesis. The focus of the research will be to understand those steps that influence the growth of initiated Cells and to define those events that lead to expression of the malignant phenotype. In classical terms, we are attempting to understand the steps of promotion and progression. Each of these projects will employ complementary approaches to understand these processes, with an emphasis on the use of murine models, chemical modifiers of carcinogenesis, and the tools of molecular genetics. The projects include: (1) Genetic modifiers of murine hepatocarcinogenesis by N. Drinkwater;and (2) Quantifying gene effects on hepatic cancer in vivo by E. Sandgren. Three modest core services (Administration, Animal Technology and Histotechnology) will support this effort. The program maintains a clear focus on hepatocellular cancers, yet, the experiments are designed so that the resultant understanding of liver cancer can be directly applicable to all types of solid tumors. Because of the unique focus and expertise of each of the co-investigators, and due to the exceptional collaborative environment generated by this PPG, the overall contributions that result from the whole program will greatly exceed the sum of the contributions that could be obtained if each project was performed in isolation. Upon completion of this proposal, it is anticipated that we will have furthered our understanding of how chemicals influence the growth controls of initiated cells within the liver. Furthermore, we will have gained molecular insights into the murine model of liver cancer that will allow us to more effectively extrapolate cancer data from animal models to the human condition.